Huntington's Disease Pathogenesis and Clinical Impact

Genetic Mechanism

The American College of Medical Genetics and Genomics states that the disease is caused by expansion of a polymorphic CAG repeat in exon 1 of the HTT gene on chromosome 4, with full penetrance occurring at ≥40 repeats and variable penetrance at 36-39 repeats 1, 2
The HTT gene expansion is inherited in an autosomal dominant manner, meaning a single copy of the mutated gene from either parent will cause disease 1, 3

The mutant huntingtin protein causes direct neurotoxicity through abnormal protein processing and aggregation, leading to selective neuronal vulnerability and death, particularly in the caudate nucleus and putamen 1, 3
Neuronal loss occurs most notably in the caudate nucleus and putamen, though the mutant protein is expressed throughout the brain and body during the entire lifetime 1, 3

The disease produces a devastating triad of progressive motor dysfunction, cognitive decline, and psychiatric disturbances over a 15-20 year course 1
There is currently no effective disease-modifying treatment, and all available therapies are purely symptomatic 1, 3, 4
Genetic testing with CAG repeat quantification provides 100% specificity for diagnosis when ≥40 repeats are present, making this a definitive molecular diagnosis rather than a clinical one 2, 4